Coatings and soaks for medical prosthetic devices comprising taurinamide derivatives and carboxylic acids and/or salts thereof

ABSTRACT

The present invention relates to a method of inhibiting or preventing infection and blood coagulation in or near a medical prosthetic device after said device has been inserted in a patient comprising administering to the device a pharmaceutically effective amount of a composition comprising: 
     (A) at least one taurinamide derivative, and 
     (B) at least one compound selected from the group consisting of biologically acceptable acids and biologically acceptable salts thereof, whereby there are no systemic anti-clotting and no systemic biocidal effects.

This application is a divisional application of U.S. Ser. No.09/552,198, filed Apr. 19, 2000, now abandoned which is a divisionalapplication of U.S. Ser. No. 09/307,916, filed May 10, 1999, now U.S.Pat. No. 6,166,007, which in turn claims priority from United StatesProvisional Application No. 60/091,491, filed Jul. 2, 1998.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a composition and method for theflushing and coating of catheters for the prevention of infection andblood coagulation.

2. Description of Related Art

Hemodialysis access systems for access to a human or animal patient'svascular system for exchange of blood between the vascular system and anexternal processing apparatus are well known in the art. One methodcomprises a catheter placed in the patient with one end extending intothe central venous system. As with any invasive procedure, theprevention of infection has been a problem, particularly with a devicethat must remain in place over protracted periods of time. Coagulationof the blood in and around the catheter has also proven troublesome andmethods are needed for its prevention, particularly with regard toinhibiting the clogging of the catheter, which can diminish or destroyits usefulness. A significant amount of research has been directed tothe alleviation of these problems.

It is standard procedure to flush catheters with an anticoagulant, suchas heparin. However, heparin is not an antibacterial and, in addition,if not carefully controlled, it can carry the anti-coagulation processtoo far, thereby presenting a risk of hemorrhage.

U.S. Pat. No. 4,096,241 discloses pharmaceutical compositions for thetreatment and for prophylaxis of tooth and gum infections, and inparticular parodontosis, comprising derivatives of thiadiazine as theactive ingredient.

U.S. Pat. No. 4,107,305 discloses a method of combating endotoxaemia byadministering an effective amount of a taurolin composition.

U.S. Pat. No. 4,337,251 discloses the use of taurolin in humans oranimals to eliminate or reduce adhesions after surgery.

U.S. Pat. No. 4,587,268 discloses a composition for the treatment ofwounds comprising a resorbable aqueous gel having dissolved or dispersedtherein one or more water-soluble medicaments, which are preferably anantibiotic or a methylol transfer antibacterial.

U.S. Pat. No. 4,587,284 discloses the preparation of an enhancedwater-absorbency hydrophilic polymer material, suitable for use in wounddressings by a process in which a water-containing organic hydrogelcomprising a gelable polysaccharide and/or protein or polypeptideinterspersed with a polymer of a hydrophilic acrylic or methacrylic acidderivative is permeated with a base, the pH of said hydrogel beingraised to at least 9 during treatment with said base.

U.S. Pat. No. 4,604,391 discloses the administration of taurolincompounds prophylactically to humans or warm-blooded animals to combatthe occurrence of osteitis or osteomyelitis, especially in patientssuffering from bone injuries of traumatic origin.

U.S. Pat. No. 4,626,536 discloses the use of taurolin compounds tocombat toxic proteins or peptides, e.g., venoms, fungal toxins andbacterial exotoxins, in the bloodstream of humans or warm-bloodedanimals.

U.S. Pat. No. 4,772,468 discloses a pharmaceutical composition forfilling into bone cavities comprising an aqueous paste formed frompowdered calcium phosphate and an antibacterial substance, if necessarytogether with one or more binders. The antibacterial substance ispreferably taurolidine and the calcium phosphate is preferablyβ-tricalcium phosphate.

U.S. Pat. No. 4,797,282 discloses a drug depot, which can be implantedin the body, for the controlled, delayed release of cytostatics,comprising a synthetic material based on polyacrylates and/orpolymethacrylates containing a cytostatic and at least one amino acid.

U.S. Pat. No. 4,853,225 discloses an implantable medicament depot usefulfor combating infections comprising physiologically acceptableexcipients and at least one delayed release active compound that is achemotherapeutic of the gyrase inhibitor type.

U.S. Pat. No. 4,882,149 discloses a pharmaceutical depot preparation forimplantation into base tissue comprising natural bone mineral from whichthe naturally associated fat and bone-proteins have been removed wherebysaid bone is sterile and non-allergenic, said bone material havingadsorbed thereon and/or absorbed therein one or more physiologicallyactive substances. The physiologically active substance isadvantageously an antibiotic or taurolidine or taurultam or a protein orpolypeptide assisting bone regeneration.

U.S. Pat. No. 4,905,700 discloses an acoustic coupling medium fortransmitting ultra-sound. The medium, which is of use in ultrasonicvisualization of the human body, comprises a sheet of hydrogelcontaining over 90% water, preferably over 95% water. The hydrogelpreferably comprises agar, the chains of which are interspersed withchains of polyacrylamide.

U.S. Pat. No. 4,960,415 discloses a device for inserting in wounds andwound cavities consisting of a container containing a pharmaceuticallyactive substance, the walls of this container consisting at least partlyof a membrane, preferably a semi-permeable membrane, which allows theactive substance to escape into the wound area. The container is, morepreferably, a dialysis tube. In order to drain off wound secretions, thecontainer containing the pharmaceutically active substance, particularlytaurolidine, is conveniently connected to a drainage tube. Preferably, adrainage tube is used in which the end that leads into the wound issplit into filaments.

U.S. Pat. No. 5,077,281 discloses the use of taurolin compounds as bloodcoagulation-inhibiting agents and as a bacterial inflammation-inhibitingagents. According to the patent, taurolin has outstandingcoagulation-inhibiting action and is especially suitable for use inmedical conditions requiring dialysis and for vascular prostheses. It isalso disclosed that these compounds can be used together with otheranti-coagulants such as coumarin or heparin.

U.S. Pat. No. 5,167,961 and 5,417,975 disclose processes for thepreparation of high purity bone mineral wherein the organic matter isdegraded by heating with ammonia or a primary amine, characterized inthat the solubilized degradation products are extracted by washing withflowing water at a temperature below 60° C., such heating with primaryamine and washing steps optionally being repeated, whereby substantiallyall organic matter removable by these steps is removed, the bone mineralso treated being heated in air at temperatures up to 700° C.

U.S. Pat. No. 5,210,083 discloses an aqueous solution containing abacterially effective concentration of taurolidine and/or taurultamtogether with a parenterally acceptable polyol. The aqueous solution issaid to be particularly suitable for parenteral administration.

U.S. Pat. No. 5,362,754 discloses pharmaceutical compositions of amixture of minocycline and EDTA (M-EDTA) and methods of using thecompositions in maintaining the patency of a catheter port. Methods forinhibiting the formation of polysaccharide-rich glycocalyx (such as theglycocalyx of staphylococcal organisms) are also provided using anM-EDTA solution. The M-EDTA solution may also be used to pretreat amedical device to prevent adherence of infectious organisms, such as S.epidermis and S. aureous. The compositions destroy and prevent theformation of polysaccharide-rich glycocalyx.

U.S. Pat. No. 5,573,771 discloses a purified particulate bone mineralproduct for use in medicine, the particles of said mineral beingsubstantially free from all endogenous organic material and having atleast at the surface thereof resorbable, physiologically compatible,natural or synthetic macromolecular material. In particular, a bonemineral is provided that is impregnated with a gel-forming protein orpolysaccharide such as gelatin to provide an increase in strength and aproduct comprising bone mineral in a matrix of collagen-fibers and agel-forming protein. Such products are intended as remodeling implantsor prosthetic bone replacement.

U.S. Pat. No. 5,593,665 discloses products containing tumor necrosisfactor and taurolidine and/or taurultam as a combined preparation forsimultaneous, separate or sequential use for treatment of patientssuffering from medical conditions mediated by tumor necrosis factor.

U.S. Pat. No. 5,603,921 discloses a medicated dental floss forcontrolling the bacterial activity associated with gingivitis. The flossincorporates an antimicrobial agent which, as a result of the flossingaction, is deposited to the interdental area of the teeth. The slowdissolution of the antimicrobial agent ensures that effective levels ofmedication are attained for sustained periods, thereby reducingbacterial activity.

U.S. Pat. No. 5,688,516 discloses compositions and methods of employingcompositions in flushing and coating medical devices. The compositionsinclude selected combinations of a chelating agent, anticoagulant, orantithrombotic agent, with a non-glycopeptide antimicrobial agent, suchas the tetracycline antibiotics. Methods for using these compositionsfor coating a medical device and for inhibiting catheter infection arealso disclosed. Particular combinations include minocycline or othernon-glycopeptide antimicrobial agent together with EDTA, EGTA, DTPA,TTH, heparin and/or hirudin in a pharmaceutically acceptable diluent.

Myers et al., J. Appl. Bacteriol 48:89-96 (1980) reported thattaurolin—bis(1,1-dioxo -perhydro-1,2,4 thiadiazinyl) methane—is anantimicrobial compound formed by the condensation of two molecules oftaurine with three of formaldehyde. It had been previously suggestedthat taurolin releases formaldehyde in contact with bacteria. Theauthors presented evidence that indicated that taurolin is mostlyhydrolyzed in aqueous solution to release one molecule of formaldehydeand two monomeric molecules, 1,1-dioxo-perhydro-1,2,4-thiadiazine andits carbinolamine derivative. According to the article, a stableequilibrium was established. The authors concluded that antibacterialactivity was not entirely due to adsorption of free formaldehyde, butalso to reaction with a masked (or latent) formaldehyde, as the activityof taurolin was found to be greater than formaldehyde. The monomer wasfound to be only slightly active by comparison.

Gorman et al., J. Clin. Pharm. Ther. 12:393-399 (1987) reported on theexamination of three antimicrobial agents, taurolidine, chlorhexidine,and povidone-iodine for microbial anti-adherence activity. Two adherencesystems were investigated: an oral isolate of Candida albicans to humanbuccal epithelial cells and a urine isolate of E. coli to humanuroepithelial cells. Each of the three agents exhibited significantanti-adherence activity, which was concentration dependent.

Root et al., Antimicrobial Agents and Chemotherapy 32(11):1627-1631(1988) reported that granulocytopenic patients with an intravascularcatheter are at increased risk for infection with S. epidermis. Duringthe intervals when the catheters are not being used for infusions, it iscustomary to maintain patency of the catheter lumen with a solutioncontaining heparin. The authors showed that heparin does not inhibit thegrowth of S. epidermis isolated from the catheter of an infectedpatient. A 20-mg/mL solution of disodium EDTA, a chelating agent thateffectively anticoagulates blood at this concentration, was shown to bebactericidal for an initial inoculum of 10³ CFU of staphylococci per mLin 24 hours. Vancomycin, an antibiotic that is often employed to treatStaphylococcus infections was also found to be bactericidal for initialinocula of 10³ CFU/mL at doses of 6.7 μg/mL, a drug concentration in thetherapeutic range. The authors recommended that EDTA be studied as areplacement for heparin solutions for the maintenance of intravenouscatheters in granulocytopenic patients, in view of its low cost,effectiveness as an anticoagulant, and bactericidal activity.

Jones et al., J. Appl. Bacteriol. 71:218-227 (1991) examined the effectsof three non-antibiotic, antimicrobial agents—taurolidine, chlorhexidineacetate, and povidone-iodine—on the surface hydrophobicity of theclinical strains E. coli, S. saprophyticus, S. epidermidis, and C.albicans. At concentrations reported to interfere withmicrobial-epithelial cell adherence, all three agents were found toalter the cell surface hydrophobicity. However, these effects failed toexhibit a uniform relationship. Generally, taurolidine andpovidone-iodine treatments decreased the hydrophobicity of the strainsexamined, whereas chlorhexidine acetate effects depended upon themicro-organism treated.

Traub et al., Chemotherapy 39:322-330 (1993) examined taurolidine forbactericidal activity against a representative number ofmultiple-antibiotic-resistant bacterial isolates in broth as well as inthe presence of bovine and human serum and fresh defibrinated humanblood. The authors suggested that this antimicrobial substance might beemployed for topical treatment of patients colonized or superficiallyinfected by glycopeptide-resistant strains of E. faecium, S. aureus(GRMRSA), or by Enterobacteriaceae producing wide-spectrum β-lactamases.

Willatts et al., Crit. Care Med. 23(6):1033-1039 (1995) reported thattaurolidine had no beneficial therapeutic effect on the outcome ofpatients admitted to the intensive therapy unit of a university teachinghospital with sepsis syndrome, using clinical, bacteriologic outcomes,progression of endotoxemia, resolution of organ failure, and 28-daymortality rate as end points.

Darouiche et al., Nutrition 13(4)(suppl):26S-29S (1997) reported thatthe prevention of vascular catheter-related infection mostly centersaround inhibiting the adherence to the catheter of microorganismsoriginating from either the skin or the catheter hub. They described twogeneral approaches that can be used non-exclusively for the successfulprevention of vascular catheter-related infection. The first approachdoes not use antimicrobial agents and includes measures such asplacement and maintenance of vascular catheters by a skilled infusiontherapy team and use of maximal sterile barriers. The second approachuses antimicrobial agents and involves the application of topicaldisinfectants such as chlorhexidine, use of silver-impregnatedsubcutaneous cuffs (for short-term central venous catheters), flushingcatheters with a combination of antimicrobial and antithrombic agents,and coating of catheters with either antiseptic (chlorhexidine andsilver sulfadiazine) or antimicrobial agents (minocycline and rifampin).

In a talk presented at the 30^(th) annual meeting of the AmericanSociety of Nephrology, held Nov. 2-5, 1997 in San Antonio, Tex.,Sodemann et al. reported on a four year trial of a gentamicin/sodiumcitrate mixture as an antibiotic-lock technique for salvage andprevention of catheter-related infections. They concluded that thereplacement of catheters due to infection can be avoided by routineapplication of the concentrated gentamicin/citrate mixture and that eventhe salvage of intraluminally contaminated catheters is possible.

Notwithstanding the above-described contributions to the art, a needcontinues to exist for a safe and effective method for the prevention ofinfection and blood coagulation in patients whose illness requires theimplantation of atrial catheters.

SUMMARY OF THE INVENTION

In accordance with the present invention, compositions are provided thatcomprise an anticoagulant and a non-antibiotic biocide, neither of whichhave the properties of (a) inducing bacterial resistance and (b) causingsystemic effects in the event of accidental overdose, i.e., there are nosystemic anti-clotting and no systemic biocidal effects.

As employed herein, the term “anticoagulant” is intended to mean anycomposition that has the ability, either directly or indirectly, toprevent the coagulation of blood or to dissolve blood clots or othercoagulated species once formed.

The biocide employed in the practice of the present invention is onethat is a “non-antibiotic,” i.e., it is not an antibiotic. For purposesof the present invention, the term “antibiotic” is defined as a chemicalsubstance produced by a microorganism that has the capacity, in dilutesolutions, to inhibit the growth of or to kill other microorganisms. Itis an object of the present invention to avoid theseantibiotics—although they may, if desired, be present in addition to thenon-antibiotics of the invention—in order to minimize the probability ofproducing microorganisms that are genetically immune thereto.antimicrobial/anti-coagulant compositions are provided for use influshing and coating medical prosthetic devices, especially cathetersand ports.

Specifically, the present invention relates to a method of inhibiting orpreventing infection and blood coagulation in or near a medicalprosthetic device after said device has been inserted in a patientcomprising administering to the device a pharmaceutically effectiveamount of a composition comprising:

(A) at least one taurinamide derivative, and

(B) at least one compound selected from the group consisting ofbiologically acceptable acids and biologically acceptable salts thereof,whereby there are no systemic anti-clotting and no systemic biocidaleffects.

More particularly, the present invention is directed to a method ofinhibiting or preventing infection and blood coagulation in or near amedical prosthetic device after said device has been inserted in apatient comprising administering to the device a pharmaceuticallyeffective amount of a composition comprising:

(A) at least one antimicrobial compound of the formula

wherein R¹ is hydrogen or alkyl and R² is hydrogen, alkyl, or a group ofthe formula

and

(B) at least one compound selected from the group consisting ofbiologically acceptable acids and biologically acceptable salts thereof.

In another embodiment, the present invention is directed to a medicalprosthetic device coated with a composition comprising:

(A) at least one antimicrobial compound of the formula

wherein R¹ is hydrogen or alkyl and R² is hydrogen, alkyl, or a group ofthe formula

and

(B) at least one compound selected from the group consisting ofbiologically acceptable acids and biologically acceptable salts thereof,wherein the composition is included in a pharmaceutically effectiveamount for preventing or inhibiting infection and blood coagulation.

In still another embodiment, the present invention is directed to amedical prosthetic device prepared by a process comprising exposing themedical prosthetic device to a composition comprising: (A) at least oneantimicrobial compound of the formula

wherein R¹ is hydrogen or alkyl and R² is hydrogen, alkyl, or a group ofthe formula

and

(B) at least one compound selected from the group consisting ofbiologically acceptable acids and biologically acceptable salts thereof,wherein the composition is included in a pharmaceutically effectiveamount for preventing or inhibiting infection and blood coagulation.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

As stated above, the present invention is directed to a method ofinhibiting or preventing infection and blood coagulation in or near amedical prosthetic device after said device has been inserted in apatient comprising administering to the device a pharmaceuticallyeffective amount of a composition comprising:

(A) at least one antimicrobial compound of the formula

wherein R₁ is hydrogen or alkyl and R² is hydrogen, alkyl, or a group ofthe formula

and

(B) at least one compound selected from the group consisting ofbiologically acceptable acids and biologically acceptable salts thereof.

The preparation of representative examples of the compounds of formula Iis described in U.K. Pat. No. 1,124,285. Basically, these compounds arecondensation products of taurinamide and formaldehyde and, therefore,will be referred to herein as “taurinamide derivatives.” They are activenot only against both gram-positive and gram-negative bacteria, but alsoagainst exotoxins and endotoxins produced by these organisms.

Where R¹ and/or R² are alkyl, they may be either straight or branchedchain alkyl and are preferably independently selected from those alkylshaving from 1 to 8 carbon atoms, i.e., methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl, and isomers thereof. More preferably,where R¹ and/or R² are alkyl, they are independently selected from thosealkyls having from 1 to methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, and isomers thereof More preferably, where R¹ and/or R²are alkyl, they are independently selected from those alkyls having from1 to 6 carbon atoms, i.e., methyl, ethyl, propyl, butyl, pentyl, hexyl,and isomers thereof; most preferably, the alkyl group(s) have from 1 to4 carbon atoms, i.e., methyl, ethyl, propyl, butyl, and isomers thereof.It is, however, most preferred that R¹ be hydrogen and that R² behydrogen or a group of formula II.

In the present invention, of the compounds of formula I, the compoundstaurolidine (R¹=H; R²=formula II) and taurultam (R¹═R²═H) areparticularly preferred. Taurolidine isbis-(1,1-dioxo-perhydroxy-1,2,4-thiadiazin-4-yl)methane.

The antimicrobial compound employed in the practice of the presentinvention is a formaldehyde carrier, i.e., a non-toxic derivativecontaining formaldehyde in combination.

The mode of action of taurolidine has been shown to include the transferof methylol groups to hydroxyl or amino groups present on the abovetoxins or on the mureine of the bacterial cell walls. In solution,taurolidine exists in equilibrium with taurultam and N-methyloltaurultam, taurolidine being greatly predominant. Taurultam is itself inequilibrium with methylol taurinamide, the equilibrium being greatly infavor of taurultam. When the above methylol derivatives, methyloltaurultam and methylol taurinamide, contact the toxins or bacteria,methylol groups are transferred. Methylol taurultam is thereby convertedto taurultam, while methylol taurinarnide is converted to taurine, anaturally occurring aminosulfonic acid that is extremely well toleratedin the human body. It will thus be appreciated that taurolidine andtaurultam act in essentially the same way and produce the same finalproducts.

Bacterial infections by gram-negative organisms are commonly accompaniedby endotoxaemia, that is, by the reaction of the patient to theendotoxin liberated by the organisms.

Endotoxin is a complex lipopolysaccharide constituent of the O-somaticantigen and is loosely attached to the cell walls of gram-negativebacteria. Irrespective of the bacterial source, all endotoxins exhibitsimilar toxic properties—in contradistinction to the exotoxins ofgram-positive bacteria, which exert a wide range of individual effects.In man, it can produce the syndrome of endotoxin shock when largenumbers of gram-negative bacteria are lysed. This syndrome isencountered in about 30% of patients with gram-negative septicaemia. Itis known that endotoxins can be inactivated by taurinamide derivatives.

Toxic proteins, such as, exotoxins, can similarly be inactivated andmethylol transfer antibacterials can be administered to combat toxicproteins in the absence of lipopolysaccharide toxins. Toxins that may beconcerned include the exotoxins of such gram-negative bacteria as E.coli and Bacteroides fragilis. It is known that intravenousadministration to mice of 0.2 mL of a 20% solution of taurolidine insterile 5% polyvinyl pyrrolidone can very significantly reduce themortality rate on intraperitoneal administration of pathogenic strainsof both E. coli and B. fragilis.

Other toxic proteins include venoms such as mellitin and fungal toxinssuch as amanitin and α-bungarotoxin, which have been shown to besubstantially detoxified by taurolidine.

A particular advantage of taurolidine is its very low toxicity; it hasbeen shown to be non-teratogenic in mice, the intraperitoneal LD₅₀ beingon the order of 1.5 g/kg. As mentioned above, these compounds exhibitmethylol transfer activity that results in the production of taurine,which is found naturally in the body and is particularly nontoxic. Afurther advantage of taurolidine is its stability in aqueous solution,enabling the solutions to be pre-packed and stored over relatively longperiods.

The taurinamide derivatives employed in the practice of the presentinvention will normally be administered as an aqueous solution byinjection into the medical prosthetic device. Such solutions maycontain, in addition to a given taurinamide derivative, gentamycinsulfate or chondroitin sulfate and also may commonly contain asolubilizing agent, such as, polyvinyl pyrrolidone (PVP), to helpmaintain the taurinamide derivative in solution and to contribute to theisotonicity of the solution. The concentration of the taurinamidederivatives in such solutions can range from greater than zero to about2 wt %; concentrations in the range of from about 0.01 to about 1.5 wt %are preferred; and a concentration of about 1 wt % is most preferred.Higher concentrations than these would be useful, but in such cases,solubility becomes a problem.

Where PVP is incorporated into the solution, it will commonly beemployed at a concentration in the range of from 4 to 7% by weight inorder to achieve relatively high concentrations of the taurinamidederivatives, especially taurolidine, which have low water solubility.The molecular weight of the PVP should not be greater that about 30,000and is preferably less than 10,000, e.g., between about 200 and 3500.Kollidone® 17, sold by BASF is especially suitable. Such PVP is fairlyquickly absorbed and excreted through the kidneys.

The amount of solution of taurinamide derivative injected into a medicalprosthetic device will be enough to fill it. Such devices, when they arehemodialysis catheters, typically have internal volumes in the range offrom about 0.1 mL to about 10 mL; such quantities will, of course, varywith the length and diameter of the tubing of the device, which, interalia, can be a function of the size of the individual patient.

The concentration of the taurinamide derivative in such solutions ispreferably in the range of from about 0.4 to about 5% by weight,depending, at the maximum, upon the solubility of the compound.Solutions of about 0.4 to about 2.0 weight % taurolidine, i.e., about 4to about 20 grams per liter, are particularly preferred.

An example describing the preparation of a stock solution of taurolidinehas appeared in several patents, for example, U.S. Pat. No. 4,337,251:

15 Liters of double distilled pyrogen free water are filled into a 25liter glass vessel equipped with a stirrer and an intensive refluxdevice and heated to 50° C. with stirring. Taurolidine (400 g) is addedfollowed by PVP (Kollidone 17; 1000 g). After dissolution, the solutionis cooled and the pH is adjusted to 6.0 with a few drops of 0.1 Nhydrochloric acid. The solution is then passed through an adsorptionfilter to remove microorganisms and pyrogens and through a sterilizingMillipore filter before being filled into 100 mL vials, which arefinally autoclaved.

If desired, some or all of the PVP may be replaced by a parenterallyacceptable polyol. This use for polyols has been disclosed in U.S. Pat.No. 5,210,083, the disclosure of which is incorporated herein byreference in its entirety. There, it is pointed out that at higherconcentrations of taurolidine, crystallization can occur, which canrender the solution unuseable.

In the case of bacteria and their endo- and exotoxins, it has been foundthat after the methylol transfer, as described above, there is a furtherirreversible step involving dehydration. Thus, in the case of bacterialendotoxins, which are lipopolysaccharides, it was found that anirreversible cross-linking reaction takes place that prevents theendotoxin from exerting its lethal effect. Similarly, in the case ofbacterial exotoxins, which are proteins or polypeptides and do notcontain lipopolysaccharide material of the kind found in the endotoxins, the detoxification reaction has been found to be irreversible.However, it is disclosed in U.S. Pat. No. 5,210,083 that the transfer ofmethylol groups by the mechanism set out above is reversible in the caseof many hydroxyl or amino compounds, so that an equilibrium can beestablished that does not significantly interfere with the availabilityof taurolidine. Thus, polyols, such as, sugars and sugar alcohols, canalso be used to maintain relatively high concentrations of taurolidineand/or taurultam in aqueous solution without significantly affectingtheir antibacterial and antitoxin activity. Preferred polyols includecarbohydrates, e.g., hexoses, such as, glucose, fructose, and mixturesthereof; pentoses, such as, xylose; polysaccharides, such as, dextran orhydrolyzed starch; glycerol; and sugar alcohols, such as, sorbitol,mannitol, and xylitol. Glucose is most preferred.

The concentration of the polyol is typically in the range of from about3 to about 40% by weight. In the case of glucose, the concentration ispreferably in the range of from about 10 to about 30% by weight, morepreferably about 20%.

Where such polyols are used, the concentration of taurolidine in thesolution is preferably in the range of from about 0.5 to about 5%, morepreferably in the range of from about 2 to about 3% by weight. Theconcentration of taurultam is preferably in the range of from about 1 toabout 7.5%, more preferably in the range of from about 3 to about 5% byweight.

Since gram-negative organisms will frequently be present and since thebacteriostatic activity of the taurinamide derivatives is lower thanthat of many conventional antibiotics, it may be advantageous toadminister the compositions employed in the practice of the presentinvention in conjunction with a broad spectrum antibiotic substance,more especially, a substance strongly active against both gram-positiveand gram-negative pathogens that, preferably, induces no or only delayedresistance, for example, a β-lactam antibiotic, such as, penicillin,ampicillin, or cephalosporin; a tetracycline antibiotic; a macrolideantibiotic, such as, erythromycin; a polypeptide antibiotic, such as,bacitracin or novobiocin; or, more preferably, an aminoglycosideantibiotic, such as, amikasin, butirosin, fortimycin, streptomycins,neomycin, linkomycins, such as, clindamycin and lincomycin, kanamycin,dideoxykanamycin B (DKP), lividomycin, netilmicin, ribostamycin,sagamycins, seldomycins and their epimers, sisomycin, sorbistin,tobramycin, vancomycin, gentamicin, and rifamycins, such as, rifampicinand rifamycin; and the like. Of these, gentamicin is preferred.

However, antibiotics are often contraindicated for use in surgicaltreatment, owing to their tendency to produce resistant strains, and,except in unusual cases, it is preferred that the taurinamide derivativebe relied upon solely for antibacterial action, since such derivativesdo not produce resistant strains.

The composition employed in the practice of the present inventionpreferably also contains a pharmacologically acceptable carriersolution, such as, water, Ringer's solution, or saline. Additionally,the compositions of the present invention can also contain otherdissolved additives that can favorably influence their physical andbiochemical properties, for example, amino acids, sugar, common salt,fats, lipids, and the like.

The antimicrobial taurinamide derivatives employed in the practice ofthe present invention are used in combination with a biologicallyacceptable acid or a biologically acceptable salt thereof. It ispreferred that the acid be a carboxylic acid and more preferred that italso be an anticoagulant. U.S. Pat. No. 5,077,281 teaches that taurolincompounds exhibit outstanding coagulation-inhibiting action in their ownright and are especially suitable for use in medical conditionsrequiring dialysis and for vascular prostheses, either alone or incombination with other anti-coagulants such as coumarin or heparin. Aspointed out in the patent, this is contrary to the teaching of“Taurolin”, published by W. L. Bruckner and R. W. Pfirrmann, VerlagUrban und Schwarzenberg, Munich, 1985, which expressly states thattaurolin does not influence blood coagulation and displays noanti-phlogistic action. It is the belief of the present inventor thatthe taurinamide derivatives employed in the practice of the presentinvention do exhibit a degree of anticoagulant activity, although to alesser extent than is found with better known anticoagulants, such asheparin. Accordingly, it is beneficial to employ the taurinamidederivatives in combination with an anticoagulant, preferably one that isa biologically acceptable acid or salt thereof.

In accordance with the present invention, beneficial results areachieved when the antimicrobial taurinamide derivatives are combinedwith a biologically acceptable acid or biologically acceptable saltthereof so as to produce a pH for the ultimate composition that is nohigher than 7, preferably in the range of from about 3.5 to about 6.5,more preferably in the range of from about 4.5 to about 6.5. Exemplaryof such acids are acetic acid, dihydroacetic acid, benzoic acid, citricacid, sorbic acid, propionic acid, oxalic acid, fumaric acid, maleicacid, hydrochloric acid, malic acid, phosphoric acid, sulfurous acid,vanillic acid, tartaric acid, ascorbic acid, boric acid, lactic acid,ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis-{β-aminoethyl ether}-N,N,N′,N′-tetraacetic acid, and diethylenetriaminepentaacetic acid, esters of p-hydroxybenzoic acid (Parabens), and thelike, and biologically acceptable salts of the foregoing, such as,ammonium phosphate, potassium citrate, potassium metaphosphate, sodiumacetate, sodium citrate, sodium lactate, sodium phosphate, and the like.A blood anticoagulating amount of an acid selected from the groupconsisting of citric acid, phosphoric acid, ethylenediaminetetraaceticacid (EDTA), ethylene glycol-bis-{β-aminoethylether}-N,N,N′,N′-tetraacetic acid, and diethylenetriamine pentaaceticacid and biologically acceptable salts thereof is preferred. It ispreferred that the acid employed in the practice of the presentinvention be an organic acid, especially one having at least onecarboxyl group, particularly citric acid or EDTA. It is more preferredthat the acid be citric acid and most preferred that it be used incombination with a citrate salt, e.g., sodium citrate, since, inaddition to its pH lowering and anticoagulation capabilities, it is alsoknown to be an antiseptic at the 3% level.

Mermel, L. A. et al., in a talk entitled Taurolidine Activity AgainstVancomycin-Intermediate Susceptibility Staphylococcus Aureus (VISA) andMethicillin-Resistant Staphylococcus Aureus (MRSA) presented at theInterscience Conference on Antimicrobial Agents and Chemotherapy (1998),disclosed that taurolidine activity increases with decreasing pH in therange of from pH 7.0 to pH 5.0.

EDTA is a known anticoagulant that is used in blood collection tubes. Itis also known to have the ability to form chelates with calcium. Sincecalcium is one factor that is known to have a role in the coagulation ofblood, it is believed possible that at least part of EDTA's efficacy inanticoagulant activity may be brought about by this means. Sodiumcitrate is also believed to have anticoagulation properties by virtue ofits ability to generate insoluble calcium citrate.

Ethylene glycol-bis-{β-aminoethyl ether}-N,N,N′,N′-tetraacetic acid(EGTA) and diethylenetriamine pentaacetic acid (DTPA) and salts thereofare other known chelating agents that can be used in place of, or inaddition to, EDTA or citric acid/citrate.

The foregoing anticoagulants can be used alone in the free acid state,but, more often will be employed with some or all of their carboxylicacid groups neutralized with an appropriate base or combined with asimilar salt. Generally, it will be desirable to employ a cation thatwill form a salt that is soluble in aqueous solution, such as alkalimetal ions, e.g., sodium, potassium, or lithium. Zinc citrate may alsobe employed. Sodium or potassium salts are normally preferred,especially sodium, and the disodium salt of EDTA and sodium citrate aremost preferred.

The acid and/or salt will be used in a concentration effective to bringabout the desired anticoagulation effect and, at the same time, bringabout, or help to bring about, an appropriate pH for biological use.Typically, the combined antimicrobial and anticoagulant composition ofthe present invention will have a pH in the range of from about 3.0 toabout 7, preferably from about 3.5 to about 6.5 and, most preferablyfrom about 4.5 to about 6.5. The composition will normally be at aphysiological pH. If necessary, the pH can be adjusted by additionalacid or base, such as a mineral acid, for example hydrochloric acid, or,preferably, one that will not cause acidosis, such as, for example,acetic, malic, or lactic acid. Other methods for adjusting the pH,familiar to those of skill in the art, can also be employed. Where, asis preferred, trisodium citrate and citric acid are employed in thepractice of the present invention, the trisodium citrate will typicallybe used in a concentration range of from about 5 to about 50 grams perliter. The citric acid will then be added in sufficient amount to bringthe pH to the desired level.

Although the process of the present invention is primarily concernedwith introducing the antimicrobial/anticoagulant compositions intocatheters that are already in place, those skilled in the art willunderstand that contacting an artificial surface outside the body withthese compositions can prevent the deposition of blood coagula on suchsurface after its implantation and aid in the elimination of sites forbacterial growth. Thus, the surfaces of medical devices, such ashemodialysis catheters, can be pre-treated by the compositions employedin the practice of the present invention to prevent the blockage due toblood coagula that present a favorable site for bacteria growth andthereby prevent the infection that may ensue. The apparatus can betreated with a composition initially and then, after insertion, repeatedperiodic flushing as referred to above.

Although the process of the present invention is primarily andpreferably directed to maintaining the patency and asepsis of implantedhemodialysis catheters, beneficial effects may also be obtained inapplying the process to other, similar, devices, such as, central venouscatheters, peripheral intervenous catheters, arterial catheters,Swan-Ganz catheters, umbilical catheters, percutaneous nontunneledsilicone catheters, cuffed tunneled central venous catheters as well aswith subcutaneous central venous ports.

Various features and aspects of the present invention are illustratedfurther in the examples that follow. While these examples are presentedto show one skilled in the art how to operate within the scope of theinvention, they are not intended in any way to serve as a limitationupon the scope of the invention.

EXAMPLE 1

A 0.5% solution of taurolidine in Ringer-lactate solution (Thomae,Biberach, Germany) was introduced into each of four polyethylene bottleshaving a 30 mL volume. Filling volumes were 5, 10, and 15 mL. One bottlewas filled with 5 mL of the taurolidine solution and 2 mL ACD-A(Fresenius, Bad Homburg, Germany) solution. ACD-A solution is used forthe conservation of whole blood and contains per liter: 22.0 grams ofsodium citrate dihydrate, 7.3 grams of citric acid and 34.5 grams ofglucose monohydrate.

Blood was collected at the slaughter house from a female pig directlyfrom the slaughter wound into the containers that were then filled up tothe 30 mL level. The containers were capped and gently moved to mixblood with the solution. The containers were inspected after 30 minutes.Blood in the containers containing only taurolidine was clotted, but theblood in the container containing the mixture of taurolidine and ACD-Awas not clotted. Thus, it is concluded that the use of sodium citrateand citric acid anticoagulants in combination with taurolidine providessubstantially enhanced anticoagulation properties in whole blood.

EXAMPLE 2

A subcutaneously implantable titanium port-system of the type describedin U.S. Pat. No. 5,954,691 is used in this example. It is connected withtwo 12 French silastic catheters introduced with the tips into the rightatrium. The valves of the port are opened by two special needlesallowing a blood flow of about 300 mL/min.

Ports were implanted by an experienced nephrologist, after theirinformed consent, in 10 female and 6 male patients, whose mean age was68±9 years. Nine of the sixteen patients were diabetics. Patientinclusion criterion for the study was vessel exhaustion resulting in noblood access sites in the arms available for hemodialysis. Eight of thesixteen suffered from severe congestive heart failure and all had a highcomorbidity. Nine of the patients started hemodialysis just afterimplantation, the others were on chronic hemodialysis and switched fromcatheter to the port system (four patient exchange by guidewire). Noperi-operative complications occurred.

The preferred vessel was the right internal jugular vein, but theexternal jugular and subclavian veins were also used. The device has,thus far, been used for a total duration of 11.0 patient years. Theports were used for all planned IID sessions (n=1200).

In order to avoid intraluminal contamination of the device, anantimicrobial lock was applied between the sessions and removed beforethe next treatment. The aqueous antimicrobial lock solution comprised13.3 grams/liter of taurolidine, 6.7 grams per liter of tri-sodiumcitrate, and approximately 3.3 grams per liter of citric acid. Thecitric acid was added to adjust the pH range to 4.75-5.25. By virtue ofthe citric acid and sodium citrate, clotting of the catheters wasprevented and application of heparin was unnecessary.

During the period of the study, two episodes of bacteriaemia (S.aureous) were observed and successfully treated without loss of thedevice (0.5 infection per 1000 days). The results of this study areshown in Table 1.

EXAMPLE 3 COMPARATIVE EXAMPLE

In four separate facilities, two in the United States and two in Europe,A, B, C, and D, studies similar to those described above in Example 2were carried out, except that the lock used was heparin or heparinizedsaline in concentrations in the range of from 2,000 to 10,000international units per mL. In the studies in the United States, A andB, benzyl alcohol was also present as a standard preservative. Theresults of these comparative studies are shown in Table 1.

TABLE 1 Infections Fibrin/Thrombosis Explant Patients Mean Mean No ofTime for Cause Affected Interval¹ Interval² Example Patients Pat. Yrs.(#s) Number (%) (Weeks) Number (Weeks) 2 31 11.0 0 2 7 286 0 >500 3A 88.0 1 6 50 70 2 208 3B 4 4.2 2 10 75 22 4 54 3C 7 6.1 2 6 43 53 4 79 3D4 3.4 0 0 0 >176 0 >176 Total 23 21.7 4 22 44 51 10 113 (Ex. 3) ¹Meaninterval without infection. ²Mean interval without clotting.

EXAMPLE 4

In this example, which is a more detailed description of the trial ofExample 2, the subcutaneously implantable titanium port-system describedin Example 2 was used.

In a prospective multi-center pilot trial starting June, 1998, 31 portswere implanted in 19 female and 12 male patients (mean age 66, min. 30,max. 81 years). In addition to the acceptance of the new device, the aimof the study was the avoidance of infection supported by the completelyatoxic mixture (heparin-free lock solution containing taurolidine as ananti-infective substance and citric acid/sodium citrate for inhibitionof coagulation) with excellent efficacy against any germs, even thosewith multi-resistance.

In ten participating centers, no port was lost since the start of thestudy (3,847 days of implantation). Despite high comorbidity, only twopatients experienced blood-stream related infections (S. aureus). Totalobserved infection was 0.5 per 1000 days. Systemic antibiotic treatmentwas successful. Pre-existing catheter-related sepsis occurred in 5/31patients; no relapse occurred in the patients using the subcutaneouslyimplantable titanium port-system.

Hospitalization was short and access was used just after implantation.The acceptance was high even in patients who switched from catheter toport (12/31). In 6/31 patients an exchange by guide-wire was possible.The usual placement technique was Seldinger applied by threenephrologists. The preferred vessel was the right internal jugular vein(18/31), but all other central veins were used.

Compared to the disadvantages of catheters, the port system allowsbathing and is very safe. Combined with the lock solution of the presentinvention, the risk of infection is low and allows a puncture techniquesimilar to a graft. The lifetime of the device has yet to beestablished.

EXAMPLE 5

An experiment was conducted to determine the minimum taurolidine/citratelock solution acidity that will function well when in contact with humanblood. Various lock solution acid concentrations were mixed 50/50 byweight with fresh whole human blood. The pH was experimentally variedfrom pH 3.0 to pH 7.0. At a lock solution acidity level of 4.0 andbelow, the resulting blood mixture becomes hard and concretionary afterone hour of contact with the lock solution. This hardening wasapparently due to the acid level of the lock solution and normal bloodclotting, since the clot appears very dark in color and dry in nature,not normal in color or physical properties. When acidity of the locksolution was maintained above pH 5.0, no blood clotting occurred andblood color remained a healthy red color. Thus, the most preferred lowerlimit for the acidity of the taurolidine lock solution is about 5.0.

In view of the many changes and modifications that can be made withoutdeparting from principles underlying the invention, reference should bemade to the appended claims for an understanding of the scope of theprotection afforded the invention.

What is claimed is:
 1. A process for treating the surface of a medicalprosthetic device to prevent or inhibit infection and blood coagulation,which comprises: exposing the surface of the prosthetic device to acomposition comprising at least one taurinamide derivative, at least onebiologically acceptable acid, and at least one biologically acceptablesalt of said acid, wherein said acid is present in sufficient amount tobring the pH of the composition into a range of from about 3.5 to about7.0.
 2. A process for treating the surface of a medical prostheticdevice to prevent or inhibit infection and blood coagulation, whichcomprises: exposing the surface of the prosthetic device to acomposition comprising at least one antimicrobial compound of theformula

wherein R1 is hydrogen or alkyl and R2 is hydrogen, alkyl, or a group ofthe formula

at least one biologically acceptable acid, and at least one biologicallyacceptable salt of said acid, wherein said acid is present in sufficientamount to bring the pH of the composition into a range of from about 3.5to 7.0; wherein the composition is included in a pharmaceuticallyeffective amount for preventing or inhibiting infection and bloodcoagulation.
 3. The process of claim 2 wherein the antimicrobialcompound is taurolidine.
 4. The process of claim 2 wherein theantimicrobial compound is taurultam.
 5. The process of claim 2 whereinthe biologically acceptable acid is selected from the group consistingof acetic acid, citric acid, fumaric acid, maleic acid, hydrochloricacid, malic acid, phosphoric acid, tartaric acid, ascorbic acid, boricacid, lactic acid, ethylenediaminetetraacetic acid (EDTA), ethyleneglycol-bis{β-aminoethyl ether}-N,N,N′, N′-tetraacetic acid anddiethylenetriamine pentaacetic acid, and the biologically acceptablesalt is selected from the group consisting of ammonium phosphate,potassium citrate, potassium metaphosphate, sodium acetate, sodiumcitrate, sodium lactate, and sodium phosphate.
 6. The process of claim 2wherein the biologically acceptable acid is citric acid and thebiologically acceptable salt is an alkali metal salt of citric acid. 7.The process of claim 2 wherein the biologically acceptable acid isethylenediaminetetraacetic acid and the biologically acceptable salt isan alkali metal salt of ethylenediaminetetraacetic acid.
 8. The processof claim 2 wherein the composition further comprises polyvinylpyrrolidone.
 9. The process of claim 2 wherein the composition furthercomprises a parenterally acceptable polyol.
 10. The process of claim 2wherein the composition further comprises a broad spectrum antibioticsubstance.
 11. The process of claim 10 wherein the broad spectrumantibiotic substance is selected from the group consisting of a β-lactamantibiotic, a tetracycline antibiotic, a macrolide antibiotic, apolypeptide antibiotic, and an aminoglycoside antibiotic.
 12. Theprocess of claim 11 wherein the broad spectrum antibiotic substance isan aminoglycoside antibiotic.
 13. The process of claim 12 wherein thebroad spectrum antibiotic substance is gentamicin.
 14. The process ofclaim 2 wherein the medical prosthetic device is a catheter.
 15. Theprocess of claim 14 wherein the catheter is a hemodialysis catheter. 16.The process of claim 2 wherein the medical prosthetic device is a port.17. The process of claim 16 wherein the port is a hemodialysis port.